Overview of Micronutrients: Iron and Folate

Omar Dary USAID–Nutrition Division/HIDN/GH

2016 Armenian

Nutrition Conference

OD-2016-09

Yerevan, Armenia

May 30th, 2016

• I am not an expert in iron and folate, but only a professional working in public health programs, who is trying to understand the reasons and origin of current recommendations.

• If something that I say does not make sense, please tell us so, and we would discuss an appropriate compromise, as our “truths” (i.e. recommendations) are limited by the advance in the reduction of our ignorance.

• I am happy to be here for learning of the science and experience of many others, especially those working with realities.

1

Disclaimers

Outline

1. What are the consequences of iron and folate deficiency? Examples of corrections.

2. Are there adverse effects due to excesses?

3. Are there biomarkers of iron and folate status? 4. How much is too little and how much is too much?

5. Then, how to add additional amounts in a safe and efficacious manner?

6. Questions and discussion. 22

3

Causes of anemia

ANEMIA

Anemia of Disease

Nutritional Anemia

IRON DEFICIENCY

Folate Deficiency

Vit B12 Deficiency

HIV/AIDS

Other

Bacteremia

Genetic Disorders

Sickle Cell Disease

G6PD Deficiency

Other hemoglobinopathies

Schistosomiasis

Parasitic Infection

Hookworm

Malaria

Other Factors Eg. Sex

Vit A Deficiency

Others

Figure produced by LM Neufeld y B Cameron, Micronutrient Initiative

• Tiredness, lack of energy • Deterioration in

detoxifying process • Impairment of the

immunological response • Irreversible cognitive

retardation (< 2 years old)

• Anemia • Maternal mortality (when

severe)

Consequences of iron deficiency

4

5 ODM-2012-6-USAC

An example of benefit by increasing iron intake in an iron-deficient population

5

Pregnant women (96 mg Fe/day; 400 µg Folic Acid/day)

Placebo + Iron

Placebo - 24 % - 29 %

+ Iron - 16 % - 19 %

Source: Angulo Barroso et al., Pediatrics 2016; 137: e20153547.

Percent of low scores of motor development at 9 months under different scenarios of iron supplementation (Hebei, China)

Infa

nts

(1 m

g Fe

/kg

from

6 w

eeks

)

6 ODM-2012-6-USAC

Iron homeostasis during pregnancy

6

Source: Cao & O’Brien, Nutr Rev 2013; 7135-51.

• Women should start pregnancy with 500 mg of stored iron • During pregnancy: + 480-1150 mg Fe • Transfer to fetus during the last 10 weeks of gestation; 270 mg Fe; 5.6 mg

Fe/day • Delayed cord clamping: until cord stops pulsing: 30% more blood volume;

60 % more iron in RBC; 75 mg iron • During third trimester of pregnancy: 3-8 mg Fe/day • Iron intake during third trimester of pregnancy? 5% bioavailability: 60 – 160 mg Fe/day 10 % bioavailability: 30 – 80 mg Fe/day 20 % bioavailability: 15 – 40 mg Fe/day • One iron receptor in human placenta (hemochromial; depend on transferrin-

bound Fe), the proton-coupled folate transporter (PCFT), shows two orders of magnitude higher affinity for folate.

Roles of folate (and other vitamins)

FA

DHF

10-CHO-THF

Purinas-CH2-

dUMP

DNA & RNA

CH3-dTMP

DNA

Homocysteine

Methionine-CH3

SA-Hcys

SAM-CH3

DIET

Proteins

DNA, RNA Lipids, hormones proteins DNA, RNA Lipids, hormones Proteins - CH3

Ser-CH2OH

Gly

Cystathionine Cysteine Ser-CH2OH

THF

5,10-CH2-THF

5-CH3-THF

Niacin

Niacin

B2 B12

B2

B6

B6

B6

Adenosine

7

Neural tube defects within 28 days after conception. Incapacities: • Leg paralysis • Hydrocephaly • Bad control of bladder and intestinal evacuations • Learning difficulties

Modified from Jorge Rosenthal

Consequences of folate (and/or B12 deficiencies)

8 8

Other consequences: • Fetal growth retardation • Low birth weight • Pre-term delivery • Macrocytic anemia • Risk to cancers: leukemia, lymphoma, colorectal, breast, prostate

Country Year Control + Min. & Vit. No Folic Acid

+ Min. & Vit. + Folic Acid

+ Folic Acid Reference

U.K. 1976 and before 470 - 70

[360 µg/d] - 1

Inter-country

1983-91 423 272 117 [4000 µg/d]

78 [4000 µg/d]

2

Ireland 1981-88 291 112 0 [360 µg/d]

0 [360 µg/d]

3

References: 1. Smithells et al., Lancet 1983; i:1027-1031. 2. MRC. Lancet 1991; 338:131-137. 3. Kirke et al., Arch Dis Child 1992; 1442-1446

Folic acid reduces recurrence of NTDs

NTD/10,000 pregnancies

9

0

10

20

30

40

50

60

70

0 200 400 600 800 1000

Additional Folic Acid (micrograms/day)

NTD/

10,0

00

0, 29

800, 0

Hungary

400,7

0, 67

North China

0,10

400,6South China

“We suggest that the trial of prevention now underway in China should be modified to contain … a low-dose arm of 400 µg or 200 µg of folic acid.” *

References: Hungary: Czeizel and Dudás N Engl J Med 1992;327:1832. China: Berry et al. N Engl J Med 1999;341:1485. * Scott JM et al. Lancet 1991;338:505.

n ∼ 2000

n ∼ 8,000 n ∼ 50,000

Prevention of first occurrence of NTDs

10

11

Impact of folic acid (2 mg/kg) through wheat flour in Chile (200 g/day of flour intake)

02468

101214161820

NTD

/10.

000

birth

s Taken from Eva Hertrampf, INTA, Chile

What other changes occurred in the Chilean population?

12

Source: Hirsch et al., J Nutr 2011.

0

5

10

15

20

25

30

35

40

4 6 8 10 12 14 16 18 20

before

after

Serum folate (µg/L*)

* µg/L x 2.266 = nmol/L

%

Def. Risk NTD Excess

Association between blood-folate and NTDs

0

10

20

30

40

0 5 10 15 20 25 30 35 40 45

Plasma folate (nmol/L)

NT

D In

cid

ence

/10,

000

Reference: Daly LE et al.,J Am Med Sci 1995;274:1698-1762.

Data from Ireland.

0

20

40

60

80

0 500 1000 1500 2000

RBC folate (nmol/L)

NT

D In

cid

ence

/10,

000

13

Serum-folate changes in USA and Chile

Adapted from Pfeiffer et al., Am J Clin Nutr 2005; 82:442-50; and Hertrampf et al., J Nutr 2003; 133:3166-69.

* Kelly et al. Am J Clin Nutr 1997;65:1790.

0

20

40

60

80

100

120

0 20 40 60 80

[plasma folate] (nmol/L)

% C

umul

ated

USA-before

USA-after

Chile-before

Chile-after

MedianMinimum Excessive

Minimum: 15.9 nmol/L Median: 25.0 nmol/L

Excessive: 45.3 nmol/L

Metabolic limit for folic acid:

266 µg/dose *

14

15

Median of serum folate (nmol/L) before and after flour fortification with folic acid

Countries Chile USA C.Rica W.Bank Ecuador Before 9 10 22 18.5-23.8

14 After 38 22 25 -

Women of child-bearing age

However, folic acid is being promoted in addition to the provision of dietary folate, as well as it is incorporated into MNP for children. Do we know that these additional amount are needed? Do we know if those are safe*?

Countries Ecuador Before

25.4 After

Children 1-5 years old Reference: National Survey of Nutrition of

Ecuador, 2013.

See: Oppenheimer & Cashin. Transactions of the Royal Society of Tropical Medicine and Hygiene 1986; 80, 169–171; Metz J. Food Nutr Bull 2007; 28(4 Suppl):S540-549.

Meta-Analysis of Trials of Iron +/- Folic Acid for Prevention or Treatment of Anemia

• All malaria settings RR 95% CI – Any parasitemia 1.13 1.01 - 1.26

• Settings with no routine malaria surveillance

– Clinical Malaria RR 95% CI Pemba 1.16 1.00 - 1.34 Five other trials 1.16 0.43 - 1.45 Total 1.16 1.03 - 1.31

Source: Ojukwu, et al, Cochrane 2009

Slide from: Robert Black, JHU, 2015

16

Adverse negative consequence of supplying iron: Severity of diarrhea in

pre-schoolers from Pakistan

17

Source: Soofi et al., Lancet 2013; 382:29-40.

Age (6-18 months)

Control MNP without zinc MNP with zinc

Incidence* RR Incidence* RR Incidence RR

Any type 3.73 1.0 4.16 1.05 (0.04-1.17)

4.16 1.05 (0.04-1.17)

Diarrhea with blood 0.08 1.0 0.16 1.63 (1.12-2.39)

0.17 1.88 ( 1.29-2.74)

Severe diarrhea (>6/d) 1.31 1.0 1.94 1.28

(1.03-1.57) 1.69 1.17

(0.95-1.45)

Persistent diarrhea 0.06 1.0 0.10 1.41 (0.87-2.28)

0.09 1.33 (0.82-2.16)

* Incidence per children-years

18 ODM-2012-6-USAC

Excessive iron supply favor pathogenic intestinal bacteria in Kenyan children

Source: Jaeggi et al., doi:10.1136/gutjnl-2014-307720 18

Probable adverse effects due to excess of folic acid

1996-1998

1997-2000

Reference: Mason J, Dickstein A, Jacques P, Haggarty P, Selhub J, Dallale G, Rosemberg I. Cancer Epidemiol Biomarkers Prev 2007; 16(7).

Other potential risks: • Masking of megaloblastic

anemia, but not other consequences of vitamin B-12 deficiency.

• Antagonist of some anti-malaria drugs (probable high levels of folic acid are required)

• Antagonist of anti-cancer medications, and eczema treatment.

• Prostate cancer.

19

The risk of unbalances

Serum folate <7 nmol/L Deficiency

Serum folate >46 nmol/L

Supra-physiological

Vit B-12 <148 pmol/L

Deficiency

B-12<148pmol/l SF>46nmol/L

Sanchez et al. Rev Med Chil 2010;938:44-52

0

5

10

15

20

25

(%

)

6.1

15.9

0.1 1.0

Risk?

Taken from Eva Hertrampf, INTA, Chile

20

Understanding biomarkers associated to nutrients

21

Amount consumed x [Nutrient] = Additional intake

FUNCTION (Tissues)

STATUS (Metabolic biomarkers)

EXPOSURE (Biomarkers of intake)

EFFECTS (Physiology changes)

Total bio-form Basal bio-form Additional bio-form

Impact requires: Need + Additional micronutrient intake + Coverage

[BIOAVAILABILITY

NUTRIENT BIOEFFICACY → &

BIOCONVERSION]

Iron Folate

IQ, endurance NTD

Anemia Anemia,

p-homocysteine

Serum- Ferritin Soluble-TfR

RBC-folate

- Serum-folate

Sens

itivi

ty

Con

foun

ding

Fac

tors

Spec

ifici

ty

FUNCTION (Tissues)

STATUS (Metabolic biomarkers)

EXPOSURE (Biomarkers of intake)

EFFECT (Physiology changes)

Micronutrient indicators: Assessing needs and impact

22

What of these are being used?

23 ODM-2012-6-USAC

Prevalence of iron deficiency in pre-schoolers using two biomarkers

Source: Namaste et al. (SPRING/USAID) Unpublished data of the BRINDA project.

Why the anemia prevalence is too different in three recent surveys in Guatemala?

24

6-8 9-11 12-17 18-23 24-35 36-47 48-59

08-09 ENSMI-2009 47.9% 40.9% 31.0%

2013 SIVESNU 10.0% 2.2% 1.5%

2015 ENSMI(DHS) 19.1% 14.8% 9.1%

Year SourceAge (months)

72.1% 58.7%

16.0%

64.3% 39.6%

25.4%

Notes: 1. The three used finger pricking and Hemo-cue, but in 2013 blood was

collected in a microtiter tube before loading the Hemo-cue cuvette. 2. In 2015 better attention was given for avoiding “milking” of the finger. 3. Question: Do we need to use different cut-off points to diagnose anemia in

small children? (WHO cut-off point is 11 g/dL from 6-59 months of age).

Cut-off of serum/plasma and RBC folate

See: Dary O. Nutritional interpretations of folic acid interventions. Nutr Rev 2009; 67:235-244.

Variable

Negative balance

(megaloblastic anemia)

Increment of homocysteine

Occurrence of NTDs

Supra-physiological

Serum Folate (nmol/L)* < 7.0 < 10.0 < 15.9 ≥ 45.3

RBC folate (nmol/L)* < 305 < 340 < 906 ?

DFE (µg/day) < 205 < 294 < 474 ≥ 1370

Folic Acid (µg/day)** < 120 < 173 < 279 ≥ 806

** Folic acid = DFE/ 1.7 25

* µg/L = nmol/L / 2.266

Variation of serum folate along the life course (years) in USA*

26

Source: Bailey et al. From NHANES, 2003-2006. J Nutr 2015; doi: 10.3945/jn.114.206599.. nmol/L = µg/L x 2.226

______ Females

------ Males

27 Figure modified from Institute of Medicine, the Academies of Science, USA..

Population minimum

Individual average

Population safety

How much is too little, and how much is too much? (adults)

28 Figure modified from Institute of Medicine, the Academies of Science, USA.. EAR, RDA/RNI,

UL values are a combination from WHO and IOM.

320, 188

420, 247

1000 Folate or folic acid: µg/d

Dietary reference intakes (DRI) of iron and folate for healthy adult females

Iron (mg/day)

Bioav. EAR RDA

5 % 25.5 58.8

10 % 13.2 29.4

20 % 6.6 14.7

UL 45 mg/day

29

Population coverage

Micronutrient content per serving size

Target fortification: Complementary foods, RUTF, RUSF, LNS

Mass fortification: flours, oil, sugar, milk, salt, rice

Supplementation: including MNP for home “fortification”

Dietary Diversity (“Nutrition”-Sensitive) – Including breast-feeding

Strategies for increasing micronutrient intakes

Supply of iron and folate by different food groups

Minerals/ Others Milk Eggs FMP1

Cereals, roots

tubers

Pulses nuts

seeds

ProVA fruits &

vgt.

Other fruits & vgt.

Oil, ref. flours, sugar

Iron - (+) +++ (++) (+++) (++) (++) -

Folate (B-9) - + + + ++++ + ++ -

Fiber - - - XX XX X XX -

Phytates - - - X XX - - -

Polyphenols - - - - XX - - -

Oxalates - - - XX -

30

Notes: 1 FMP = Fish, meat, poultry; X = relative density, non-nutrient; + = Relative density of the micronutrient.; ( ) low absorption in humans

Comparison of micronutrient- delivering strategies

31

Characteristic Diet Food Fortification Supplementation

Principle Increase nutrient content through selection and appropriate combination of foods

Incorporation of micronutrients to the edible vehicles during the manufacturing process

Syrups/tablets/powders of micronutrients consumed with/without foods (home- “fortification”)

Impact Additional quantity and quality of the supplied micronutrients (very little to do with the mechanism of delivery)

PROGRAMMATIC EFFICIENCY (Sustainability)

Feasible √ √√ √√√

Easy to deliver √√ √√√ √

Accessed by consumers √√ √√√ √

Practical to monitor √ √√ √√√

Viable total cost. √√√ √√ √